Project Summary: Ventricular tachyarrhythmias are responsible for 300,000 sudden cardiac deaths a year in the US. The mechanisms underlying these arrhythmias in the majority of cases are ventricular tachycardia (VT) and/or ventricular fibrillation (VF). The ever-increasing prevalence of obesity also poses a significant burden on the health care system with increased morbidity and mortality. Importantly, obesity has been associated with cardiac arrhythmias with increased risk of sudden cardiac death linked to increased adiposity. However, the mechanisms by which obesity could result in ventricular arrhythmias (VT/VF) remain incompletely understood. In this proposal, I plan to use a multimodal and multiscale approach to characterize VT/VF in donor human hearts associated with sustained obesity. In the mentored phase of this project, I will use donor hearts to investigate the role of epicardial adiposity in promoting VT/VF via paracrine signaling, while also getting specialized training in bioinformatics and adipocyte biology. In the independent phase of this project, I will use donor hearts to investigate the role of epicardial adiposity in generating arrhythmogenic triggers. The experiments outlined below will advance our understanding of VT/VF mechanisms and also serve as proof-of-concept for future experiments designed to develop new markers to predict and treat VT/VF vulnerability in a clinical setting.